Norepinephrine concentration was higher in guinea-pig liver than in rat or mouse liver and evidence was obtained that the norepinephrine was present within nerves. In guinea pigs, norepinephrine in liver was depleted by reserpine, 6-hydroxydopamine and metaraminol. The depletion by 6-hydroxydopamine and metaraminol was antagonized by prior treatment with desipramine, an inhibitor of uptake into norepinephrine neurons. Guinea-pig liver concentrated metaraminol to a greater extent than did rat liver; the concentration of metaraminol was lowered by desipramine pretreatment and, within three tissues of the guinea pig (heart greater than liver greater than muscle), paralleled the concentration of endogenous norepinephrine. These findings constitute pharmacological evidence for noradrenergic innervation of guinea-pig liver to a greater extent than in other species. Histofluorescence studies confirmed the existence of norepinephrine-containing nerve terminals in guinea-pig liver. Norepinephrine-containing varicosities were seen adjacent to the hepatic artery, portal vein and bile duct in the portal spaces and adjacent to sinusoid capillaries and hepatocytes in the liver parenchyma. These findings strengthen the evidence for sympathetic innervation of liver and suggest the guinea pig as a useful species in exploring physiological roles of noradrenergic innervation of liver.